153559-76-3

Usage

Uses

Used in Pharmaceutical Industry:
6-[1-(3,5,5,8,8-PENTAMETHYL-5,6,7,8-TETRAHYDRO-NAPHTHALEN-2-YL)-CYCLOPROPYL]-NICOTINIC ACID is used as a potent RXR agonist for the treatment of non-insulin-dependent (type II) diabetes mellitus (NIDDM). Its agonistic properties on the retinoid X receptor (RXR) play a crucial role in modulating the metabolic pathways and improving insulin sensitivity in patients with type II diabetes.
Additionally, due to its chemical structure and properties, it may have potential applications in other areas of pharmaceutical research, such as the development of new drugs targeting other metabolic disorders or diseases. However, further research and development would be required to explore these possibilities.

Biochem/physiol Actions

LG100268 (LG268) is a potent and selective rexinoid and retinoid-X receptor (RXR) agonist. LG100268 binds to the α, β and γ RXR receptors with an IC50 = 3-4 nM and has no activity at the RAR retinoic acid receptors.

InChI:InChI=1/C24H29NO2/c1-15-12-18-19(23(4,5)9-8-22(18,2)3)13-17(15)24(10-11-24)20-7-6-16(14-25-20)21(26)27/h6-7,12-14H,8-11H2,1-5H3,(H,26,27)

Upstream product

• 1620061-17-7 4,4,5,5-tetramethyl-2-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)-1,3,2-dioxaborolane 
• 1347735-37-8 ethyl 6-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)nicotinate 
• 17610-24-1 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalenyl)ethanone 
• 153559-92-3 methyl 6-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]nicotinate 
• 153559-44-5 methyl 6-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethenyl]nicotinate 
• 169124-35-0 6-chlorocarbonyl-nicotinic acid methyl ester 
• 6683-48-3 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene 
• 6223-78-5 2,5-dichloro-2,5-dimethyl hexane 
• 881-86-7 dimethyl 2,5-pyridine dicarboxylate 
• 110-03-2 2,5-dimethyl-2,5-hexanediol 
• 153559-50-3 methyl 6-<1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl>nicotinate 
• 17874-79-2 pyridine-2,5-dicarboxylic acid 5-methyl ester 

Relevant academic research and scientific papers

Bromomethyl Silicate: A Robust Methylene Transfer Reagent for Radical-Polar Crossover Cyclopropanation of Alkenes

A general protocol for visible-light-induced cyclopropanation of alkenes was developed with bromomethyl silicate as a methylene transfer reagent, offering a robust tool for accessing highly valuable cyclopropanes. In addition to α-aryl or methyl-substituted Michael acceptors and styrene derivatives, the unactivated 1,1-dialkyl ethylenes were also shown to be viable substrates. Apart from realizing the cyclopropanation of terminal alkenes, the methyl transfer reaction has been further demonstrated to be amenable to the internal olefins. The photocatalytic cyclopropanation of 1,3-bis(1-arylethenyl)benzenes was also achieved, giving polycyclopropane derivatives in excellent yields. With late-stage cyclopropanation as the key strategy, the synthetic utility of this transformation was also demonstrated by the total synthesis of LG100268.

A masked diboron in Cu-catalysed borylation reaction: Highly regioselective formal hydroboration of alkynes for synthesis of branched alkenylborons

The use of a masked diboron as a boron source in the presence of a Cu-N-heterocyclic carbene (NHC) catalyst enables alkyl-, aryl-, heteroatom- and silyl-substituted terminal alkynes to undergo α-selective formal hydroboration to give diverse branched alkenylboron compounds exclusively. Synthetic potential of this α-selective hydroboration has been demonstrated by total synthesis of pharmaceutically significant bexarotene and LG100268. This journal is the Partner Organisations 2014.

THERAPEUTIC COMPOUNDS

The invention provides compounds of formulae (I), (II), (III), and (IV): and salts thereof, as well as pharmaceutical compositions comprising such compounds. The compounds are useful for treating cancers and Alzheimer's disease.

Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,

Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8- tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6- pentamethylnaphthalen-7-yl)-4-hydr

ABC EXPRESSION PROMOTERS

The ABCA1 mRNA expression-promoting agent, LXRα mRNA expression-promoting agent, ABCG1 mRNA expression-promoting agent, cholesterol efflux-promoting agent, cholesteryl ester accumulation-inhibiting agent, ACAT-1 mRNA expression-inhibiting agent and CEH mRNA expression-promoting agent of the present invention are excellent in the ability to control cholesterol distribution in the body and have low toxicity.

Agent for improving ketosis

An agent for improving ketosis which comprises an insulin sensitizer, which has an excellent action and low toxicity.

Assay for identification of compounds that promote melanin production and retinoid-like compounds identified by said assay

An in vitro assay for selecting compounds that alter pigmentation of skin is provided. Also, a novel class of pro-pigmentatory compounds is provided which comprise substituted aromatic or heterocyclic carboxylic acids, or derivatives thereof, or pharmaceutically acceptable salts, which do not contain a pheno, naphthol, thiophenol, or a thionaphthol function in free or protected form. In a preferred embodiment, thess compounds will display activity for RXRs. These compounds may be used for altering pigmentation of human skin and/or hair in cosmetic or dermatological compositions, and for the treatment of disorders and disease conditions that affect skin or hair pigmentation.

Synthesis of novel retinoid X receptor-selective retinoids

Retinoids 1-5 have been identified as potent RXR agonists for evaluation in the treatment of non-insulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of 1-5 have been developed. The core tetrahydronaphthalene 7, employed in the synthesis of 1 and 2, was prepared in 98% yield using an AlCl3-catalyzed (0.03 equiv) Friedel-Crafts alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane 6. A nitromethane-mediated Fridel-Crafts acylation of 7 with chloromethylnicotinate 9 was developed to prepare ketone 10 in 68% yield. Chelate-controlled addition of MeMgCl to 10 followed by dehydration afforded olefin 11 in 65% yield. Cyclopropanation of 11 with trimethylsulfoxonium ylide, followed by saponification, completed a five-step synthesis of 1 in 33% yield. FeCl3-catalyzed (0.05 equiv) Friedel-Crafts acylation of 7 with chloromethyl-terephthalate 14 afforded ketone 15 in 81% yield. Saponification of 15 and reaction with 50% aqueous NH2OH in AcOH afforded a 9:1 mixture of cis and trans oximes, from which the desired cis-oxime 2 was isolated in 43% yield. The core bromo-dihydronaphthalene 29 required for the synthesis of 3-5 was prepared by a Shapiro reaction. Transmetalation of 29 and reaction with Weinreb amides 30b or 36 afforded ketones 32 and 37, which were converted into 3-5 using chemistry comparable to the tetrahydronaphthylene series. Suzuki coupling of boronic acids 41 and 42 with vinyl triflate 43 provided an alternative approach to the synthesis of this class of compounds.

Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells

Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.